Characteristics and outcome of patients with second primary lung cancer

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1 ORIGINAL ARTICLE LUNG CANCER Characteristics and outcome of patients with second primary lung cancer Niels Reinmuth 1,2, Andreas Stumpf 1, Patrick Stumpf 1, Thomas Muley 2,3, Sonja Kobinger 2,3, Hans Hoffmann 2,3, Felix J.F. Herth 2,4, Philipp A. Schnabel 2,5, Arne Warth 2,5, Helge Bischoff 1,2 and Michael Thomas 1,2 Affiliations: 1 Depts of Thoracic Oncology, Thoraxklinik, University of Heidelberg, Heidelberg, 2 Translational Lung Research Center Heidelberg, German Center for Lung Research, Heidelberg, 3 Thoracic Surgery, Thoraxklinik, University of Heidelberg, Heidelberg, 4 Pneumology and Respiratory Critical Care Medicine, Thoraxklinik, University of Heidelberg, Heidelberg, and 5 Institute of Pathology, University of Heidelberg, Heidelberg, Germany. Correspondence: N. Reinmuth, Lung Clinic Grosshansdorf, Department of Thoracic Oncology, Wöhrendamm 80, D Grosshansdorf, Germany. Nielsreinmuth@gmx.net ABSTRACT Patients with lung cancer are at risk of developing a second primary lung cancer (SPLC). However, the characteristics of patients at risk remain largely speculative. We reviewed 2816 lung cancer patients from our institution for the occurrence of SPLC. Any SPLC was categorised as synchronous when diagnosed within 2 years of the first primary lung cancer (FPLC) and after direct histological comparison of both tumours. All other SPLCs were considered as metachronous. 139 patients developed a second malignancy including 69 nonsmall cell lung cancer (NSCLC) and 9 small cell lung cancer. The median interval for diagnosis of metachronous SPLC (n559) after FPLC occurrence was 72 months. SPLC detected within 5 years of FPLC diagnosis had a more favourable stage distribution (p50.02). After diagnosis of SPLC, patients had a superior median overall survival compared to controls (57.7 versus 18.1 months; p,0.0001). Interestingly, comparing only stage IV NSCLC patients, a history of FPLC was also associated with a favourable survival (median 27.4 versus 8.97 months; p50.007). In summary, previous lung cancer treatment does not lead to impaired prognosis after diagnosis of SPLC. Improved surveillance programmes beyond 5 years after FPLC treatment may result in more favourable disease stages for detected Previous lung cancer treatment does not lead to impaired prognosis after diagnosis of secondary primary lung cancer Received: Feb Accepted after revision: Aug First published online: Oct Conflict of interest: None declared. Copyright ßERS Eur Respir J 2013; 42: DOI: /

2 Introduction Lung cancer remains one of the most frequent human cancers and the leading cause of cancer-related deaths in the western world [1]. Since most lung cancer patients present with advanced or metastatic disease, the overall 5-year survival rate is only 15% [1]. However, after or during treatment for lung cancer, patients may develop another malignancy, including a second primary lung cancer (SPLC). Some authors have described an increased risk of developing SPLC for lung cancer patients which has been attributed largely to the risks of tobacco consumption [2 4]. The incidence of SPLC has been reported at 1 2% per patient-year [5, 6]. Still, relatively few data have been published about this selected group of patients with sometimes conflicting results. Most of these data have been generated in the 20th century and included low patient numbers, derived either from multiple institutions or over a long time period, that may have rendered conclusions difficult as a result of varying diagnostic procedures and therapeutic developments. Moreover, data regarding clinical characteristics is lacking for patients with first primary lung cancer (FPLC) who might be at risk for developing SPLC. Current surveillance programmes of lung cancer patients do not specifically address the risk of developing a second malignancy [7, 8]. Hence, we conducted a retrospective analysis of SPLC patients diagnosed and treated in our institution within a defined and recent time interval. Methods Patients Retrospectively, we reviewed all lung cancer patients who were treated in our institution between January 1, 2004, and December 31, 2006 using the hospital information system and medical records. In addition, and upon approval by the local ethics committee, patients or their treating physicians were contacted, and the follow-up statuses were completed. The staging of lung cancer was performed according to the sixth edition of TNM (tumour, node, metastasis) criteria; however, all data was also analysed using the seventh TNM classification. Lung cancer patients without a second malignancy served as the control group. The smoking status was assessed at diagnosis of the SPLC. In agreement with other studies, former smoking status was defined for patients with a nicotine cessation of at least 6 months [9, 10]. Patients with a total consumption of less than 100 cigarettes were classified as never-smokers. Definition of a second primary lung tumour To identify two lung primary tumours as independent, the criteria established by MARTINI and MELAMED [11] and ANTAKLI et al. [6] were used. Briefly, tumours with the same histology must have either an interval of at least 2 years, originate from carcinoma in situ or be located in different lungs, lobes or segments without common lymphatics and without distant metastases to be considered as independent primaries. In a similar manner to previous studies, synchronous SPLC was identified if an independent SPLC was evident within 2 years after diagnosis of the FPLC [5, 11]. For synchronous cancers with similar histology, the occurrence of an independent SPLC was confirmed by an independent pathologist after histological TABLE 1 Locations of a second malignancy after diagnosis of lung cancer Location of second malignancy First primary lung cancer NSCLC SCLC Total Another lung cancer 69 (55.6) 9 (60.0) 78 (56.2) Head neck 8 (6.5) 2 (13.3) 10 (7.2) Kidney 2 (1.6) 2 (13.3) 4 (2.9) Bladder 9 (7.4) 0 9 (6.5) Oesophagus 1 (0.8) 0 1 (0.7) Colon 6 (4.8) 1 (6.7) 7 (5.0) Rectum 4 (3.2) 0 4 (2.9) Breast 5 (4.0) 1 (6.7) 6 (4.3) Ovary 1 (0.8) 0 1 (0.7) Liver 4 (3.2) 0 4 (2.9) Pancreas 2 (1.6) 0 2 (1.4) Adrenal gland 1 (0.8) 0 1 (0.7) Prostate 8 (6.5) 0 8 (5.8) Melanoma 2 (1.6) 0 2 (1.4) Skin cancer other than melanoma 2 (1.6) 0 2 (1.4) Total 124 (100) 15 (100) 139 (100) Data are presented as n (%). NSCLC: nonsmall cell lung cancer; SCLC: small cell lung cancer. DOI: /

3 comparison of both tumours. An independent SPLC discovered later than 2 years was labelled metachronous. Follow-up after therapy of FPLC All patients entered a follow-up programme with 3-monthly visits for the first 2 years, 6-monthly visits after 2 5 years and yearly visits thereafter [7]. In addition, SCLC patients were seen every 2 months for the first year. All follow-up visits included physical examination, lung function tests and a chest radiograph. In surgically treated patients, a computed tomography scan was performed every 6 months for the first 2 years. Statistical analysis The census date was fixed after a minimum period of follow-up of at least 46 months for each patient. As end-points, we used the date of death or survival at the last documented contact with the patient. Collectively, a total of 6326 person-years (4638 person-years for males and 1688 person-years for females) of observation were noted. Patients who died of causes other than lung cancer were censored. Quantitative variables were summarised with their mean or median. Two-sided analysis of variance and the Chi-squared test were performed where appropriate. Survival curves of the different subgroups are presented according to the Kaplan Meier method. Throughout, p,0.05 was considered to be statistically significant. Results A total of 139 patients with a second malignancy after diagnosis of lung cancer were identified (table 1) resulting in a prevalence of 2.41% per patient-year. Among these, 78 patients developed a SPLC (prevalence 1.33% per patient-year; 65 nonsmall cell lung cancer (NSCLC) and 13 small cell lung cancer (SCLC); table 2). In 19 patients, SPLCs were diagnosed synchronously. For metachronous SPLCs, the median (range) interval between diagnosis of FPLC and SPLC was 72 ( ) months with most SPLC diagnosed after 5 years of FPLC diagnosis. In contrast, a group of 2675 lung cancer patients developed no further malignancy and served as the control group. While the current health status could not be updated TABLE 2 Patient characteristics Characteristics Patients with SPLC Control group Patients Age at time of diagnosis of FPLC Median age years Age range years Age distribution f29 years years years years years years o80 years 0 97 Sex Male Female Smoking status Current smoker 47 (61.8) 1473 (74.0) Former 18 (23.7) 372 (18.7) Never 11 (14.5) 146 (7.3) Unknown Median pack-years Interval FPLC SPLC,1 month months 2 6 months 1 year years years years years 17 Data are presented as n or n (%), unless otherwise stated. FPLC: first primary lung cancer; SPLC: second primary lung cancer DOI: /

4 for 471 patients (11 patients with SPLC; 460 patients in the control group) the mean follow-up was 26.1 months for all patients (median 15.4 months) and 43.9 months for surviving patients (median 43.6 months). Characteristics of FPLC Of the 78 patients who later developed a SPLC, 69 and nine patients had a previous NSCLC and SCLC, respectively. Compared to controls, the median age of patients with FPLC was younger (58 versus 64 years in controls). Interestingly, while significantly more FPLC patients were former and never-smokers (p,0.05), those patients who did smoke had a higher median cigarette consumption (55 versus 47.5 packyears; p,0.01). Since most FPLCs were diagnosed in early stages (table 3), most patients underwent surgical resection (86%) or radiation therapy of FPLC (26%). No FPLC was treated with chemotherapy alone. All three first primary NSCLC patients with stage IV disease had lung metastases (ipsilateral in two patients; contralateral in one patient) as the only metastasis location and underwent complete resection of both the primary tumour and metastases, followed by chemotherapy in two cases. One SCLC patient with brain metastasis, that was treated with chemotherapy and cerebral radiation, developed a SPLC after 7 years. Characteristics of SPLC At diagnosis of SPLC (65 NSCLC, 13 SCLC), the median (range) age was 64 (45 81) years which was similar to controls. NSCLC and SCLC as metachronous SPLC were diagnosed after a median interval of 77 ( ) and 67 (29 226) months after diagnosis of FPLC, respectively. There were no significant differences between synchronous and metachronous SPLC. All but one SCLC developed as metachronous cancer. No patient with SCLC as FPLC developed another SCLC as a SPLC. In cases of adenocarcinoma or squamous cell carcinoma as FLPC, 65% and 46% of patients also had a similar histology as SPLC, respectively (table 4). Similar to FPLC, most SPLC were diagnosed as stage I (51.3%) and stage II (11.5%) disease which was independent from the stage of FPLC. Interestingly, SPLC disease detected within or after 5 years after TABLE 3 Disease and treatment characteristics FPLC SPLC Control group Histology NSCLC 69 (88.5) 65 (11.5) 2188 (81.8) Adenocarcinoma Squamous cell carcinoma Large cell carcinoma NSCLC, not specified SCLC 9 (11.5) 13 (16.7) 487 (18.2) Stage distribution NSCLC I 40 (57.9) 38 (58.5) 544 (24.9) II 14 (20.3) 6 (9.2) 166 (7.6) III 12 (17.3) 11 (16.9) 733 (33.5) IV 3 (4.3) 10 (15.4) 745 (34.0) Stage distribution SCLC I 1 (11.1) 2 (15.4) 36 (7.4) II 0 3 (23.1) 11 (2.3) III 7 (78,8) 3 (23.1) 226 (46.4) IV 1 (11.1) 5 (38.4) 214 (43.9) Initial treatment Surgery only Radiation therapy only Chemotherapy only Combination therapy Surgery and chemotherapy Surgery and radiation therapy Radiation therapy and chemotherapy All modalities No treatment Data are presented as n or n (%). FPLC: first primary lung cancer; SPLC: second primary lung cancer; NSCLC: nonsmall cell lung cancer; SCLC: small cell lung cancer. DOI: /

5 TABLE 4 Development of second primary lung cancer (SPLC) with regard to the histology of the first primary lung cancer (FPLC) FPLC SPLC Histology n Histology n Adenocarcinoma 31 Adenocarcinoma 20 Squamous cell carcinoma 7 Large cell carcinoma 2 SCLC 2 Squamous cell carcinoma 28 Adenocarcinoma 6 Squamous cell carcinoma 13 Large cell carcinoma 0 SCLC 9 Large cell carcinoma 8 Adenocarcinoma 4 Squamous cell carcinoma 2 Large cell carcinoma 0 SCLC 2 SCLC 9 Adenocarcinoma 2 Squamous cell carcinoma 5 Large cell carcinoma 2 SCLC 0 NSCLC, NOS 2 Adenocarcinoma 1 Squamous cell carcinoma 1 Large cell carcinoma 0 SCLC 0 Total SCLC: small cell lung cancer; NSCLC: non-small cell lung cancer; NOS: not otherwise specified. diagnosis of FPLC had a different stage distribution (p50.02; table 5). While SPLC was detected as stage I disease in 65% of cases when diagnosed within 5 years of FPLC detection, this stage was only present in 34% when diagnosed after 5 years of FPLC. In contrast, SPLC was diagnosed as stage III/IV disease in 30% and 46%, respectively, when detected within or after 5 years of FPLC. The most frequent localisation of SPLC was the left upper lobe (35.1%) while FPLC was most often found in the right upper lobe (47.4%). In comparison, lung cancers of the control group were located in the left and right upper lobes in 26.1% and 29.5%, respectively. Compared to FPLC, stage I and II SPLC underwent less frequent surgical resection (78% versus 98%) but were treated more often with radiotherapy (29% versus 7%). Of all stage IV SPLC patients, two patients had single lung metastases that were completely resected with the primary tumour. Another patient had brain metastases and received radiation of both the thoracic tumour and brain metastases. Two stage IV patients could not be offered treatment due to poor performance status. All other stage IV patients (n510) were treated with systemic chemotherapy alone. Survival SPLC patients had a median overall survival of 12.6 years (95% CI months) and 4.8 years (95% CI months) determined from the date of diagnosis of FPLC and SPLC, respectively. In comparison, the control group had a median survival of 1.5 years ( months; p,0.0001). At the end of data bank closure, 46 (59%) patients with SPLC were still alive including 11 patients who were lost to follow-up. Interestingly, the survival benefit for SPLC compared to controls held true for smokers (median 57.7 versus 18.1 months; p50.01) but not for former (p50.11) or never smokers (p50.14). Patients with synchronous SPLC had a better overall survival after diagnosis of SPLC compared to metachronous SPLC patients (median not reached versus 42.6 months; p,0.05). While the survival of SPLC patients with SCLC was not significantly different from controls (median 16.3 versus 13.3 months; p50.64), patients with NSCLC as SPLC lived more than four times longer after SPLC diagnosis than NSCLC control patients (median not reached versus 19.8 months, p,0.0001; fig. 1). Comparing NSCLC patients with similar disease stages, a history of FPLC was associated with superior survival for patients with stage IIIA (median versus 26.5 months; p50.001) and stage IV disease (median 27.4 versus 8.97 months; p50.006; fig. 2). When all cancers were reclassified using the seventh 1672 DOI: /

6 TABLE 5 Stage distribution of second primary lung cancer depending on the time interval after diagnosis of first primary lung cancer Stage Interval,5 years Interval.5 years I 28 (65) 12 (34) II 2 (5) 7 (20) III 6 (14) 8 (23) IV 7 (16) 8 (23) Data are presented as n (%). TNM classification, the difference in overall survival for SPLC NSCLC patients versus controls held true (median not reached versus 8.8 months; p50.007). However, SPLC patients with stage IV disease (both NSCLC and SCLC) receiving only chemotherapy were not significantly different to the respective control patients (10 versus 650 patients; p50.14). Patients with additional malignancies Besides developing a SPLC, eight patients (10.2%; six male, two female) developed a third malignancy after the FPLC including a third primary lung cancer (two patients), melanoma (two patients), prostate cancer and sarcoma (one patient each). In two cases, the origin of the third malignancy remained unknown. At the end of data bank closure, five of these patients were still alive. Discussion To our knowledge, this report reflects on the largest number of patients with SPLC from a single institution with uniform staging and diagnosis criteria. The prevalence of a second malignancy in all lung cancer patients investigated in our study was 2.41% per patient-year, which was somewhat higher compared to data from a large survey including cancer patients (5799 with lung cancer) from from a Japanese institution [12]. In this study, the risk for second malignancy was 0.008% and 1.87% per patientyear for all cancer patients or lung cancer patients only, respectively. Compared to expected values in the general population, the risk of developing a SPLC was 4.6 and 7.8 times higher for male and female patients with lung cancer, respectively. Since 1962, progress in diagnostic and therapeutic options such as the introduction of adjuvant chemotherapy after complete resection has influenced the general outcome of lung cancer with a possible impact on the occurrence of second malignancies. In our study with 2004 as the start entry for collecting data, second primaries were most often located in the lung (55% as compared to only 45% for all other organ cancers combined). In comparison, only 11.04% of all tumour patients being diagnosed in Germany in 2006 had lung cancer [13]. The risk of 1.33% per patient-year for developing a SPLC is in congruence with the estimate of 1 2% per year after the diagnosis of FPLC in other studies [4, 5]. Some authors described a higher risk of SCLC patients for developing a SPLC [2, 14] as compared to the risk for SPLC after NSCLC [5]. However, we did not detect significant differences in this regard. 100 Patients with SPLC Control group 80 FIGURE 1 Survival of nonsmall cell lung cancer (NSCLC) patients with or without a second primary lung cancer (SPLC). NSCLC patients with a history of a previous primary lung cancer had a significantly superior survival compared to control patients without previous malignancy and diagnosed in the same time interval (p,0.0001). Survival % Years DOI: /

7 Patients with SPLC Control group Survival % Years FIGURE 2 Survival of stage IV nonsmall cell lung cancer (NSCLC) patients with and without a second primary lung cancer (SPLC). Patients with SPLC (n510) had a significantly improved survival after diagnosis of the SPLC compared to controls (n5745; p50.006). Patients with SPLC and a smoking history had a significantly higher cigarette consumption compared to controls, which is similar to previous data [15]. In accordance with other data, the predominant histology of SPLC after SCLC was squamous cell carcinoma [14, 16] which may also indicate high nicotine consumption as a risk factor. Collectively, high nicotine consumption remains a major risk factor especially in those patients who continue cigarette smoking after diagnosis of lung cancer [17, 18]. There is an ongoing discussion on the arbitrary distinction between synchronous and metachronous SPLC [19, 20]. In our study, 24% of SPLCs were diagnosed as synchronous tumours. We followed most previous studies in using the definition by MARTINI and MELAMED [11]. Moreover, in cases of similar histology, histological sections from both FPLC and SPLC were compared. This approach may have contributed to a lower incidence of synchronous SPLC compared to others who described approximately one third of all SPLC patients as synchronous [21, 22]. However, the histological pattern may have been changed in relapse tumours. As a perspective, a better identification of the independence of lung primaries may involve molecular assessments such as gene array analyses or patterns of loss of heterozygosity. In a limited number of synchronous and metachronous pulmonary tumours, assessment of loss of heterozygosity patterns demonstrated that the previous classification of synchronous and metachronous tumours based on the criteria suggested by MARTINI and MELAMED [11] held true for most, but not all cases [23]. Most metachronous SPLCs were diagnosed 5 years after diagnosis of the FPLC which is somewhat similar to two retrospective studies on surgical patients developing metachronous SPLC [24 26]. Interestingly, and previously unaddressed, SPLC disease was detected in a more advanced stage when diagnosed more than 5 years after diagnosis of FPLC compared to SPLC patients with a shorter interval. This may have been the consequence of the extension of follow-up visits to a yearly schedule. However, whether a more frequent surveillance programme after 5 years may have led to diagnosis of more SPLC in earlier stages remains speculative and would need to be addressed in larger clinical studies [5]. The 5-year survival rate of 44% of all SPLC patients in our study is congruent with data from 41 resected patients with metachronous lung cancer [26]. Some studies on patients with surgically treated metachronous SPLC report somewhat lower outcomes despite recruiting only patients with early tumour stages (26% 33%) [27, 28]. The finding of earlier studies that support a worse prognosis for patients with synchronous lung tumours compared to metachronous tumours could not be confirmed in our study [6, 26]. Compared to our control group, patients lived significantly longer after SPLC diagnosis, an effect that, at least in part, may be explained by positive patient selection. SPLC patients had more favourable disease stages and were more often never or former smokers. Moreover, one should also consider competing risks caused by major comorbidities, in particular pulmonary and cardiovascular diseases. While this data could not be evaluated for the current manuscript, future evaluations should address this issue as well as possible long-term side-effects caused by the previous treatments. Comparing the outcome of similar disease stages between NSCLC patients with and without SPLC, stage IV SPLC patients had a significantly better overall survival that held true even after reanalysis using the seventh TNM classification for all lung cancers. Comparing only stage IV NSCLC patients receiving exclusively chemotherapy, the superior outcome failed significance possibly due to low patient numbers. In contrast, the survival of patients after diagnosis of SCLC as SPLC was not different to control patients. Again, the case numbers were low. As a hypothesis, metastatic disease may rather reflect the biology of the disease 1674 DOI: /

8 compared to limited stages treated with surgery or radiation. Since various epigenetic and genetic alterations may modify lung cancer risk and development, the better overall survival of patients with SPLC may indicate a distinct epigenetic profile [29, 30]. Reflecting the opportunity of a favourable outcome, as shown in the recent analysis, SPLC should be attributed to an as best treatment approach. As examples of such an approach selected stage IV NSCLC patients with solitary adrenal gland, brain or contralateral lung metastasis did benefit from complete resection of both primary lung tumour and metastasis resulting in a favourable outcome [31 33]. Moreover, according to the revised staging system, patients with ipsilateral lung metastasis are now classified as having T4 tumours [34]. In summary, our data suggest that lung cancer patients should be closely monitored after treatment with possibly shorter intervals beyond 5 years. Patients with multiple or recurrent thoracic tumours should be carefully staged and, if justifiable depending on expected risks for the patient, be re-biopsied in order to distinguish SPLC from recurrent FPLC. The prognosis of SPLC patients does not seem to be worse compared to other patients with lung cancer and may even be superior in certain circumstances [35]. References 1 Jemal A, Siegel R, Ward E, et al. Cancer statistics, CA Cancer J Clin 2008; 58: Tucker MA, Murray N, Shaw EG, et al. Second primary cancers related to smoking and treatment of small-cell lung cancer. Lung Cancer Working Cadre. J Natl Cancer Inst 1997; 89: van Bodegom PC, Wagenaar SS, Corrin B, et al. Second primary lung cancer: importance of long term follow up. Thorax 1989; 44: Levi F, Randimbison L, Te VC, et al. Second primary cancers in patients with lung carcinoma. Cancer 1999; 86: Johnson BE. Second lung cancers in patients after treatment for an initial lung cancer. J Natl Cancer Inst 1998; 90: Antakli T, Schaefer RF, Rutherford JE, et al. Second primary lung cancer. Ann Thorac Surg 1995; 59: Goeckenjan G, Sitter H, Thomas M, et al. Prevention, diagnosis, therapy, and follow-up of lung cancer: interdisciplinary guideline of the German Respiratory Society and the German Cancer Society. Pneumologie 2010; 65: Azzoli CG, Baker S Jr, Temin S, et al. American Society of Clinical Oncology Clinical Practice Guideline update on chemotherapy for stage IV non-small-cell lung cancer. J Clin Oncol 2009; 27: Coultas DB, Howard CA, Peake GT, et al. Discrepancies between self-reported and validated cigarette smoking in a community survey of New Mexico Hispanics. Am Rev Respir Dis 1988; 137: Barbone F, Bovenzi M, Cavallieri F, et al. Cigarette smoking and histologic type of lung cancer in men. Chest 1997; 112: Martini N, Melamed MR. Multiple primary lung cancers. J Thorac Cardiovasc Surg 1975; 70: Kobayashi Y, Arimoto H, Watanabe S. Occurrence of multiple primary cancer at the National Cancer Center Hospital, Jpn J Clin Oncol 1991; 21: Robert Koch-Institut, Gesellschaft der epidemiologischen Krebsregister in Deutschland e.v. Krebs in Deutschland 2005/2006. Häufigkeiten und Trends [Cancer in Germany 2005/2006]. Berlin, Robert Koch-Institut, Available from: 14 Johnson BE, Cortazar P, Chute JP. Second lung cancers in patients successfully treated for lung cancer. Semin Oncol 1997; 24: Sugimura H, Watanabe S, Tsugane S, et al. Case-control study on histologically determined multiple primary lung cancer. J Natl Cancer Inst 1987; 79: Smythe WR, Estrera AL, Swisher SG, et al. Surgical resection of non-small cell carcinoma after treatment for small cell carcinoma. Ann Thorac Surg 2001; 71: Gritz ER, St Jeor ST, Bennett G, et al. National working conference on smoking and body weight. Task Force 3: implications with respect to intervention and prevention. Health Psychol 1992; 11: Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 1953; 6: Ribet M, Dambron P. Multiple primary lung cancers. Eur J Cardiothorac Surg 1995; 9: Paci M, Sgarbi G, Annessi V, et al. Multiple primary lung cancers: comment on current opinions. Lung Cancer 2003; 39: Deschamps C, Pairolero PC, Trastek VF, et al. Multiple primary lung cancers. Results of surgical treatment. J Thorac Cardiovasc Surg 1990; 99: Riquet M, Cazes A, Pfeuty K, et al. Multiple lung cancers prognosis: what about histology? Ann Thorac Surg 2008; 86: Huang J, Behrens C, Wistuba I, et al. Molecular analysis of synchronous and metachronous tumors of the lung: impact on management and prognosis. Ann Diagn Pathol 2001; 5: Doddoli C, Thomas P, Ghez O, et al. Surgical management of metachronous bronchial carcinoma. Eur J Cardiothorac Surg 2001; 19: Lee BE, Port JL, Stiles BM, et al. TNM stage is the most important determinant of survival in metachronous lung cancer. Ann Thorac Surg 2009; 88: Aziz TM, Saad RA, Glasser J, et al. The management of second primary lung cancers. A single centre experience in 15 years. Eur J Cardiothorac Surg 2002; 21: van Rens MT, Zanen P, de la Riviere AB, et al. Survival after resection of metachronous non-small cell lung cancer in 127 patients. Ann Thorac Surg 2001; 71: Faber LP. Resection for second and third primary lung cancer. Semin Surg Oncol 1993; 9: DOI: /

9 29 Risch A, Plass C. Lung cancer epigenetics and genetics. Int J Cancer 2008; 123: Yang IV, Schwartz DA. Epigenetic control of gene expression in the lung. Am J Respir Crit Care Med 2011; 183: Tanvetyanon T, Robinson LA, Schell MJ, et al. Outcomes of adrenalectomy for isolated synchronous versus metachronous adrenal metastases in non-small-cell lung cancer: a systematic review and pooled analysis. J Clin Oncol 2008; 26: Voltolini L, Rapicetta C, Luzzi L, et al. Surgical treatment of synchronous multiple lung cancer located in a different lobe or lung: high survival in node-negative subgroup. Eur J Cardiothorac Surg 2010; 37: Melloni G, Bandiera A, Gregorc V, et al. Combined treatment of non-small cell lung cancer with synchronous brain metastases: a single center experience. J Cardiovasc Surg (Torino) 2011; 52: Rami-Porta R, Ball D, Crowley J, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the T descriptors in the forthcoming 7th edn of the TNM classification for lung cancer. J Thorac Oncol 2007; 2: Vansteenkiste JF, De Belie B, Deneffe GJ, et al. Practical approach to patients presenting with multiple synchronous suspect lung lesions: a reflection on the current TNM classification based on 54 cases with complete follow-up. Lung Cancer 2001; 34: DOI: /